Melanoma therapy

ABSTRACT

Methods for treating treatment-naive as well as treatment-experienced patients having melanoma to increase the progression-free survival time involving administering a therapeutically effective amount of pegylated interferon-alpha, e.g., preferably pegylated interferon alpha-2b, as adjuvant therapy to definitive surgery are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 09/545,312 filedApr. 7, 2000 (now abandoned) which is a non-provisional application thatclaims the priority of U.S. provisional patent application Ser. No.60/128,308 filed Apr. 8, 1999. The Applicants' claim the benefits ofthese applications under 35 U.S.C. §§19(e) and 120.

Throughout this disclosure, various publications, patents and patentapplications are referenced. The disclosures of these publications,patents and patent applications are herein incorporated by reference.

BACKGROUND OF THE INVENTION

This invention relates to an improved therapy for treating patientshaving melanoma after definitive surgical removal of the lesions byadministering a therapeutically effective dose of pegylatedinterferon-alpha for a time sufficient to increase progression-freesurvival time.

Melanoma incidence is increasing at a rate that exceeds all that forother solid tumors. Patients with primary melanoma of greater than 4 mmor metastatic melanoma involving regional lymph nodes possess a 50 to90% mortality risk following surgical excision of the primary melanomas.

Recently, the Eastern Cooperative Oncology Group (“ECOG”) publishedresults of the use of interferon alpha-2b in patients with stage IIIcutaneous melanoma as adjuvant therapy following surgery for deepprimary (T4) or regionally metastatic (N1) melanoma (Kirkwood, J. M., etal. J. Clin. Oncol., Vol 14: (1996) pages 4-17.) The interferon alpha-2btherapy used by ECOG involved an induction phase of 20 million IU ofinterferon alpha-2b per square meter of body surface area (m²)administered intravenously (“IV”) daily for five days every week forfour weeks followed by maintenance interferon alpha therapy of 10million IU/m² administered subcutaneously (“SC”) three times a week(“TIW”) for 48 weeks. A significant improvement in median disease-freesurvival and overall survival were observed versus control (observation)despite dosage reductions or delays for toxicity in 50% of the patientsduring the IV induction therapy phase and in 48% of the patients in theSC maintenance phase. Hematologic, neurologic and constitutionaltoxicities occurred among these patients requiring dose reduction orwithdrawal from the interferon alpha therapy. Subject compliance withthe dosage and dosage regimen during both phases is considered to beimportant to achieve maximum clinical benefit. Accordingly, there is aneed for improved therapy for treating patients having melanoma withhigher patient compliance.

SUMMARY OF THE INVENTION

The present invention provides a method of treating a patient havingmelanoma which has been surgically removed, which comprisesadministering to such a patient a therapeutically effective dose ofpegylated interferon alpha for a time period sufficient to increase theprogression-free survival time.

The present invention also provides a method of treating a patienthaving cutaneous melanoma which has been surgically removed, whichcomprises administering to said patient an effective amount of pegylatedinterferon-alpha once a week for a time period sufficient to increaseprogression-free survival time.

The present invention further provides a method of treating a patienthaving cutaneous melanoma which has been surgically removed whichcomprises administering to such a patient about 3.0 micrograms/kg toabout 9.0 micrograms/kg of pegylated interferon alpha-2b once a week fora time period sufficient to increase progression-free survival time. Inpreferred embodiments, 6.0 micrograms per kilogram is dosed weekly to apatient for eight weeks, and 3.0 micrograms per kilogram or less weeklyis dosed to the patient for a period of five years minus the eight weeksof initial dosage. If less than 3.0 micrograms per kilogram are dosed tothe patient, preferably the dose reduction steps are 3.0-2.0-1.0micrograms per kilogram.

The present invention further provides a method comprising the step ofmarketing a therapeutically effective dose of interferon alpha foradministration to a patient with melanoma within about 60 days ofsurgery in a protocol extending for a time period of at least about 100weeks.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved method of treating patientswith melanoma especially those in State IIB (lesions>4 mm, but withoutpositive nodes)and Stage III (lesions>4 mm and node-positive) primarycutaneous melanoma, preferably after surgery for their State IIB orStage III melanoma. The improved method provides a safer and moreefficacious and tolerable adjuvant therapy treatment for melanoma by useof weekly injections of pegylated interferon. The melanoma patientstreatable in accordance with the improved method of the presentinvention include those newly diagnosed with this disease who were freeof disease 56 days post surgery but at high risk for systemic recurrenceof the disease. The term “high risk patients” as used herein means thosemelanoma patients with lesions of Breslow thickness>4 mm as well asthose patients with lesions of any Breslow thickness with primary orrecurrent nodal involvement. Melanoma patients intolerant or resistantto interferon alpha therapy are also included. Treatment with pegylatedinterferon alpha in accordance with the present invention will continuefor a minimum of about two years (about 100-104 weeks) and up to fiveyears, unless there is clinical evidence of disease progression,unacceptable toxicity or the patient requests that the therapy bediscontinued.

When the pegylated interferon-alpha administered is a pegylatedinterferon alpha-2b, the therapeutically effective amount of pegylatedinterferon alpha-2b administered is in the range of about 3.0 to about9.0 micrograms per kilogram of pegylated interferon alpha-2badministered once a week (QW), preferably in the range of about 4.5 toabout 6.5 micrograms per kilogram of pegylated interferon alpha-2b QW,more preferably in the range of about 5.5 to about 6.5 micrograms perkilogram of pegylated interferon alpha-2b QW, and most preferably in therange of about 6.0 micrograms per kilogram of pegylated interferonalpha-2b administered QW.

In preferred embodiments, 6.0 micrograms per kilogram is dosed weekly toa patient for eight weeks, and 3.0 micrograms per kilogram or lessweekly is dosed to the patient for a period of five years minus theeight weeks of initial dosage. If less than 3.0 micrograms per kilogramare dosed to the patient, preferably the dose reduction steps are3.0-2.0-1.0 micrograms per kilogram.

When the pegylated interferon-alpha administered is a pegylatedinterferon alpha-2a, the therapeutically effective amount of pegylatedinterferon alpha-2a administered is in the range of about 50 microgramsto about 500 micrograms once a week (“QW”), preferably about 200micrograms to about 250 micrograms QW.

The term “pegylated interferon alpha” as used herein means polyethyleneglycol modified conjugates of interferon alpha, preferably interferonalpha-2a and -2b. The preferred polyethylene-glycol-interferon alpha-2bconjugate is PEG₁₂₀₀₀-interferon alpha 2b. The phrases “12,000 molecularweight polyethylene glycol conjugated interferon alpha” and“PEG₁₂₀₀₀-IFN alpha” as used herein mean conjugates such as are preparedaccording to the methods of International Application No. WO 95/13090and containing urethane linkages between the interferon alpha-2a or -2bamino groups and polyethylene glycol having an average molecular weightof 12000.

The preferred PEG₁₂₀₀₀-interferon alpha-2b is prepared by attaching aPEG polymer to the epsilon amino group of a lysine residue in the IFNalpha-2b molecule. A single PEG₁₂₀₀₀ molecule is conjugated to freeamino groups on an IFN alpha-2b molecule via a urethane linkage. Thisconjugate is characterized by the molecular weight of PEG₁₂₀₀₀ attached.The PEG₁₂₀₀₀-IFN alpha-2b conjugate is formulated as a lyophilizedpowder for injection. The objective of conjugation of IFN alpha with PEGis to improve the delivery of the protein by significantly prolongingits plasma half-life, and thereby provide protracted activity of IFNalpha.

The term “interferon-alpha” as used herein means the family of highlyhomologous species-specific proteins that inhibit viral replication andcellular proliferation and modulate immune response. Typical suitableinterferon-alphas include, but are not limited to, recombinantinterferon alpha-2b such as Intron-A interferon available from ScheringCorporation, Kenilworth, N.J., recombinant interferon alpha-2a such asRoferon interferon available from Hoffmann-La Roche, Nutley, N.J.,recombinant interferon alpha-2C such as Berofor alpha 2 interferonavailable from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield,Conn., interferon alpha-n1, a purified blend of natural alphainterferons such as Sumiferon available from Sumitomo, Japan or asWellferon interferon alpha-n1 (INS) available from the Glaxo-WellcomeLtd., London, Great Britain, or a consensus alpha interferon such asthose described in U.S. Pat. Nos. 4,897,471 and 4,695,623 (especiallyExamples 7, 8 or 9 thereof and the specific product available fromAmgen, Inc., Newbury Park, Calif., or interferon alpha-n3 a mixture ofnatural alpha interferons made by Interferon Sciences and available fromthe Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.The use of interferon alpha-2a or alpha-2b is preferred. Sinceinterferon alpha-2b, among all interferons, has the broadest approvalthroughout the world for treating chronic hepatitis C infection, it ismost preferred. The manufacture of interferon alpha-2b is described inU.S. Pat. No. 4,530,901.

Other interferon alpha conjugates can be prepared by coupling aninterferon alpha to a water-soluble polymer. A non-limiting list of suchpolymers include other polyalkylene oxide homopolymers such aspolypropylene glycols, polyoxyethylenated polyols, copolymers thereofand block copolymers thereof. As an alternative to polyalkyleneoxide-based polymers, effectively non-antigenic materials such asdextran, polyvinylpyrrolidones, polyacrylamides, polyvinyl alcohols,carbohydrate-based polymers and the like can be used. Such interferonalpha-polymer conjugates are described in U.S. Pat. Nos. 4,766,106,4,917,888, European Patent Application No. 0 236 987, European PatentApplication Nos. 0 510 356 , 0 593 868 and 0 809 996 (pegylatedinterferon alpha-2a) and International Publication No. WO 95/13090.

Pharmaceutical composition of pegylated interferon alpha-suitable forparenteral administration may be formulated with a suitable buffer,e.g., Tris-HCl, acetate or phosphate such as dibasic sodiumphosphate/monobasic sodium phosphate buffer, and pharmaceuticallyacceptable excipients (e.g., sucrose), carriers (e.g. human serumalbumin), toxicity agents (e.g. NaCl), preservatives (e.g. thimerosol,cresol or benylalcohol), and surfactants(e.g. tween or polysorabates) insterile water for injection. The pegylated interferon alpha-may bestored as lyophilized powders under a refrigeration at 2°-8° C. Thereconstituted aqueous solutions are stable when stored between 2° and 8°C. and used within 24 hours of reconstitution. See for example U.S. Pat.Nos. 4,492,537; 5,762,923 and 5,766,582. The reconstituted aqueoussolutions may also be stored in prefilled, multi-dose syringes such asthose useful for delivery of drugs such as insulin. Typical suitablesyringes include systems comprising a prefilled vial attached to apen-type syringe such as the NOVOLET Novo Pen available from NovoNordisk, as well as prefilled, pen-type syringes which allow easyself-injection by the user. Other syringe systems include a pen-typesyringe comprising a glass cartridge containing a diluent andlyophilized pegylated interferon alpha powder in a separate compartment.

The term “patients having melanoma” as used herein means any patienthaving melanoma and includes treatment-naive patients as well astreatment-experienced patients as well as patients in the Stage IIB orStage III cutaneous melanoma. All patients having melanoma arepreferably treated by wide excision of the primary melanoma lesion priorto initiation of the improved therapy of the present invention.

The term “treatment-naive patients” as used herein means patients withmelanoma including newly-diagnosed melanoma patients who have never beentreated with any chemotherapeutic drugs, e.g. dacarbazine (“DTIC”) orimmunotherapy, e.g., IL-2 as well as any interferon, including but notlimited to interferon alpha, or pegylated interferon alpha. Alltreatment-naive patients having melanoma are preferably treated by wideexcision of the primary melanoma lesion prior to initiation of theimproved therapy of the present invention.

The term “treatment-experienced patients” as used herein means thosepatients who have initiated some form of chemotherapeutic drug, e.g.,DTIC or immunotherapy including, but not limited to interferon-alpha,IL-2 and GMCSF. All treatment-experienced patients having melanoma arepreferably treated by wide excision of the primary melanoma lesion priorto initiation of the improved therapy of the present invention.

The term “primary cutaneous melanoma” as used herein meanshistologically proven primary cutaneous melanoma as defined by thecurrent (1992) American Joint Committee on Cancer Staging Criteria(“AJCC”): in the AJCC Manual for Strategy of Cancer (4th edition)Philadelphia Pa. Lippincott Publishers 1992 and includes (a) nodenegative stage IIB disease with deep primary melanomas of Breslow depthmore than 4 mm and (b)node positive stage III disease defined, asfollows: (1) deep primary melanomas of Breslow depth more than 4 mm(designated CS1 PS1: T4N0M0); (2) primary melanomas of any tumor stagein the presence of N1 regional lymph node metastasis detected atelective lymph node dissection with clinically inapparent regional lymphnode metastasis (designated CS1 PS2: any TpN1M0); (3) clinicallyapparent N1 regional lymph node involvement synchronous with primarymelanoma of T1-4 (designated CS2 PS2: any TcN1M0); and (4) regionallymph node recurrence at any interval after appropriate surgery forprimary melanoma of any depth (designated CS2R: TxrN1M0 recurrent).Patients in groups 1 to 3 were required to enter this study within 56days of first primary melanoma biopsy. Patients with regional nodalrelapse in group 4 were required to enter this study within 42 days oflymphadenectomy.

All patients with stage III melanoma should be treated by wide excisionof the primary melanoma lesion.

Patients with clinically positive nodes in the groin, axilla or neckshould have a full lymphadenectomy to surgically remove these cites.

All surgery should be completed within 56 days prior to randomizationinto this clinical study.

The term “progression-free survival time” (“PFST”) as used herein meansthe time from initiation of melanoma treatment in accordance with thepresent invention to the documentation of disease progression orrecurrence by histological or cytological evidence.

The progression-free survival time expected for melanoma patientstreated in accordance with the method of this invention is at leastabout 4 years from initiation of the melanoma therapy of this invention;preferably the PFST is in the range of about 30 to about 43 months frominitiation of the melanoma therapy of this invention.

The increase in the progression-free survival time expected for melanomapatients treated in accordance with the method of this invention isgreater than about 1.0 years to about 1.5 years compared to control(observation).

The following criteria of treatment failure constitute the onlyacceptable evidence of disease recurrence or progression:

Lung/Liver:

Positive cytology or biopsy in the presence of a single new lesion orthe appearance of multiple lesions consistent with metastatic disease.

Central Nervous System:

A positive brain CT or MRI scan or Cerebrospinal fluid (CSF) cytology.

Cutaneous, Subcutaneous and Lymph Node Recurrence:

Positive cytology or biopsy.

Bone and Other Organs:

Positive cytology or biopsy in the presence of a single new lesion orthe appearance of multiple lesions consistent with metastatic diseaseidentified by two different radiologic studies: i.e., positive galliumscan and contrast GI series or ultrasound, x-ray or CT of abdomen forabdominal disease.

The term “prohibited medications” as used herein includes the following:

-   -   a) Other chemotherapy, hormonal, immunologic, biologic or        radiation therapy.    -   b) Colony stimulating factors including erythropoietin and        G-CSF.    -   c) Other investigational drugs.    -   d) Chronic systemic corticosteroid therapy.

Melanoma patients treated in accordance with the method of the presentinvention should not receive any of the above-listed prohibitedmedications during the treatment period.

Pegylated interferon-alpha formulations are not effective whenadministered orally, so the preferred method of administering thepegylated interferon-alpha is parenterally, preferably by subcutaneous,IV, or IM, injection. Of course, other types of administration of bothmedicaments, as they become available are contemplated, such as by nasalspray, transdermally, by suppository, by sustained release dosage form,and by pulmonary inhalation. Any form of administration will work solong as the proper dosages are delivered without destroying the activeingredient.

The following Clinical Study Design may be used to treat melanomapatients in accordance with the method of the present invention. Manymodifications of this Clinical Study Design protocol will be obvious tothe skilled clinician, and the following Study Design should not beinterpreted as limiting the scope of the method of this invention whichis defined by the claims listed hereinafter.

Clinical Study Design

This is a Phase II/III randomized, controlled, multicenter, open-labelstudy designed to assess he safety, efficacy, and impact on quality oflife of PEG Intron (pegylated interferon alpha 2b i.e.PEG₁₂₀₀₀-interferon alpha 2b and INTRON® A (interferon alpha 2b), whichare each available from Schering Corporation, Kenilworth, N.J., and thepopulation pharmacokinetics of PEG Intron when given as adjuvant therapyin subjects with resected Stage III node-positive cutaneous melanoma. Itis anticipated that approximately 450 subjects will be enrolled, with225 subjects randomized to each treatment group.

Subjects will enter the study within 56 days of definitive surgery fortheir Stage III melanoma and will be randomized to one of the twotreatment groups shown below. Definitive surgery includes wide surgicalexcision of the primary melanoma and lymphadenectomy of all clinicallypositive nodes in the groin, axilla and neck. All surgery should becomplete at least 56 days prior to randomization.

Group A: INTRON® A

20 MIU/m²/day IV 5 days/week×4 weeks, followed by 10 MIU/m² SC TIW×48weeks.

Induction Therapy: 20 MIU/m²/day IV 5 days a week for 4 weeks

All subjects randomized to Treatment Group A, will begin inductiontherapy with intravenous INTRON® A, 20 million internationalunits/m²/day, 5 days/week for 4 weeks. Acetaminophen (500-1000 mg) maybe given in the clinic 30 minutes prior to receiving the first dose ofINTRON® A. Subjects should be observed for 2 hours after the first dose.Acetaminophen (500-650 mg PO q 4-6 hours) should be continued as needed,and should not exceed 3000 mg/day.

Maintenance Therapy: 10 MIU/m² SC TIW for 48 weeks.

After induction therapy, subjects will continue on maintenance therapyand receive INTRON® A, 10 million international units/m²/day, SC threetimes weekly for 48 weeks.

Group B: PEG Intron: PEG₁₂₀₀₀-interferon alpha-2b, 6.0 pg/kg, SC onceweekly for 2 years.

Subjects randomized to treatment Group B will receivePEG₁₂₀₀₀-interferon alpha-2b, 6.0 μg/kg, SC once weekly for 2 years.Acetaminophen (500-1000 mg) may be given in the clinic 30 minutes priorto receiving the first dose of PEG Intron. Subjects should be observedfor 2 hours after the first dose. Acetaminophen (500-650 mg PO q 4-6hours) should be continued as needed, and should not exceed 3000 mg/day.

Duration of Study and Visit Schedule

Treatment with either PEG₁₂₀₀₀-interferon alpha 2b (about 104 weeks) orINTRON® A (52 weeks) will continue as scheduled unless there isevidenced of disease recurrence, unacceptable toxicity, or the subjectrequests that therapy be discontinued. Tolerability of the respectivestudy treatment and quality of life will be assessed from clinicalobservation, routine lab oratory testing, and quality of lifeassessments over the course of therapy. Following completion of therapy,subjects will continue to be followed for evidenced of diseaserecurrence and will complete quality of life assessments. If themelanoma recurs, further treatment will be at the discretion of thephysician. All subjects will be followed for survival, regardless ofwhen they discontinue therapy. Analyses of relapse-free and overallsurvival, regardless of when they discontinue therapy. Analyses ofrelapse-free and overall survival will be event driven.

The duration of this study is based upon achieving a therapeuticresponse, and will be determined for each subject individually.

The study population will include male and female patients withcutaneous melanoma and will be included if they meet the followinginclusion and exclusion criteria:

Subject Inclusion Criteria

A subject is eligible to participate in this study if he or she:

-   a) Subjects must have histologically documented primary cutaneous    melanoma meeting one of the following staging criteria:    -   Primary melanoma of any stage in the presence of N1 regional        lymph node metastases detected at elective lymph node dissection        or sentinel node biopsy, with clinically inapparent regional        lymph node metastasis (any PTN₁M₀).    -   Clinically apparent N1 or N2a regional lymph node involvement        synchronous with primary melanoma of T₁₋₄ (any pTrN_(1-2a)M₀).    -   Regional lymph node recurrence at any interval after appropriate        surgery for primary melanoma of any depth (any pTrN_(1-2a)M₀)-   b) Subjects must have had all known disease completely resected with    adequate surgical margins within 56 days prior to randomization into    the study.-   c) Subjects must have an ECOG performance status of 0 or 1 as    defined by Minna, J D, et al. “Cancer of the Lung” in DeVita V, et    al. eds., Cancer: Principles and Practiced of Oncology, Lippincott,    Philadelphia, Pa. 1989 at page 536.-   d) Subjects must be between 18-70 years old.-   e) Subjects must have adequate hepatic, renal and bone marrow    function as defined by the following parameters obtained within 14    days prior to initiation of study treatment.    -   1) Hematology:        -   White Blood count (WBC) ≧3,000 cells/μL.        -   Hemoglobin concentration ≧9 g/dL.    -   2) Renal and hepatic function:        -   Serum creatinine ≦2.0 mg/dL or calculated creatinine            clearance of ≧50 mL/minute.        -   Serum bilirubin <2 times the upper limit of normal (ULN),            unless due to infiltration by disease.        -   AST/ALT (SGOT/SGPT) <2 times ULN.-   f) has submitted a written voluntary informed consent before study    entry, is willing to participate in this study and will complete all    follow up assessments.

Subject Exclusion Criteria

A subject is not eligible to participate in this study if he or she:

-   a) Subjects who have received any prior chemotherapy, immunotherapy    hormonal or radiation therapy for melanoma.-   b) Subjects who have evidence of distant or non-regional lymph node    metastases, in-transit metastases, or positive lymph nodes with an    unknown primary.-   c) Subjects whose disease cannot be completely surgically resected    because of gross extracapsular extension.-   d) Subjects who have previously received interferon-α for any    reason. (Such patients however, are still considered treatable in    accordance with the method of this invention but are only excluded    from this registration study.)-   e) Subjects who have severe cardiovascular disease, i.e.,    arrhythmias requiring chronic treatment, congestive heart failure    (NYHA Class III or IV) or symptomatic ischemic heart disease as    defined by Bruce R A: Evaluation of Functional Capacity and Exercise    Tolerance of Cardiac Subjects” in Mod. Concepts Cardiovasc Dis 1956;    25-321.-   f) Subjects who have a history of neuropsychiatric disorder    requiring hospitalization.-   g) Subjects with thyroid dysfunction not responsive to therapy.-   h) Subjects with uncontrolled diabetes mellitus.-   l) Subjects with a history of prior malignancy within the past 5    years other than surgically cured non-melanoma skin cancer or    cervical carcinoma in situ.-   j) Subjects who have a history of seropositivity for HIV.-   k) Subjects who are pregnant, lactating, or of reproductive    potential and not practicing an effective means of contraception.-   l) Subjects with active and/or uncontrolled infection, including    active hepatitis.-   m) Subjects with a medical condition requiring chronic systemic    corticosteroids.-   n) Subjects who are known to be actively abusing alcohol or drugs.-   o) Subjects who have received any experimental therapy within 30    days prior to randomization in this study.-   p) Subjects who have not recovered from the effects of recent    surgery.

Subject Discontinuation Criteria

It is the right and duty of the clinical investigator to interrupt thetreatment of any subject whose health or well being may be threatened bycontinuation in this study.

Subjects may be discontinued prior to completion of this study for anyof the following reasons:

-   a) Develops documented progression or recurrence of disease, as    defined herein above.-   b) Has a clinically significant adverse event as determined by the    Principal Investigator.-   c) Requests to be withdrawn from the study.-   d) Is unable to complete the study evaluations/visits because of    unforeseen circumstances.-   e) Develops other conditions for which, in the investigator's    opinion warrants withdrawal from the study-   f) Develops severe depression or any other psychiatric disorder    requiring hospitalization.-   g) Experiences a serious allergic response to the study drug    manifested by angioedema, bronchoconstriction or anaphylaxis.-   h) Receives treatment with a prohibited medication as indicated    herein above.-   l) Experiences recurrent toxicities despite dose modifications as    described herein below.

All subjects will be followed for survival, regardless of when they gooff study. Subjects who discontinue for reasons other than recurrence ofdisease should also be followed for recurrence and survival.

Analysis of Primary and Secondary Endpoints

The primary endpoint will be progression-free survival (PFS) time,defined to be the time from randomization to progression or death. PFSwill be assessed by clinical observation, with recurrence documented byappropriate radiographic and histologic methods, and confirmed byIndependent Central Review.

The secondary endpoints will be overall survival, safety, quality oflife, and population pharmacokinetics (PK). Safety and tolerability willbe assessed from clinical observation and routine laboratory testingover the course of therapy. Health-Related Quality of Life (HQL) will beassessed from an HQL questionnaire.

Population pharmacokinetics will be assessed from periodic serumsampling in the PEG Intron group.

Subjects enrolled in Group A who are not able to tolerate the IVinduction dose regimen despite dose modification, should stop the IVregimen but should not be discontinued from the study. After resolutionof toxicity, they may enter the INTRON® A maintenance phase with thefull maintenance dose.

1. A method of treating a patient having melanoma which has beensurgically removed, which comprises administering to such a patient atherapeutically effective weekly dose of PEG₁₂₀₀₀ interferon alpha for atime period sufficient to increase progression-free survival time;wherein the therapeutically effective weekly dose of PEG₁₂₀₀₀ interferonalpha administered is selected from the group consisting of about 3.0micrograms/kg to 9.0 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b andabout 200 micrograms to 250 micrograms of PEG₁₂₀₀₀ interferon alpha-2a.2. The method of claim 1 wherein the patient is a treatment-naivepatient.
 3. The method of claim 2 wherein the treatment-naive patient isone having newly diagnosed melanoma.
 4. The method of claim 1 whereinthe patient is a treatment-experienced patient.
 5. The method of claim 4wherein the treatment experienced patient is intolerant to interferonalpha or resistant to interferon alpha.
 6. The method of claim 1 whereinthe time period is at least about 24 months.
 7. The method of claim 1wherein the therapeutically effective weekly dose of PEG₁₂₀₀₀ interferonalpha administered is about 3.0 micrograms/kg to 9.0 micrograms/kg ofPEG₁₂₀₀₀ interferon alpha-2b.
 8. The method of claim 7 wherein thetherapeutically effective weekly dose of PEG₁₂₀₀₀ interferon alpha-2b isabout 4.5 to about 6.5 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b. 9.The method of claim 8 wherein the therapeutically effective weekly doseof PEG₁₂₀₀₀ interferon alpha-2b is about 5.5 to about 6.5 micrograms/kgof PEG₁₂₀₀₀ interferon alpha-2b.
 10. The method of claim 9 wherein thetherapeutically effective weekly dose of PEG₁₂₀₀₀ interferon alpha-2b isabout 6.0 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b.
 11. The methodof claim 10 further comprising a dose reduction step such that 6.0micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b is administered once aweek for eight weeks, and then 3.0 or less micrograms/kg of PEG₁₂₀₀₀interferon alpha-2b is administered once a week for the remainder of afive year treatment period.
 12. The method of claim 11 wherein the dosereduction step is to 3 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2bonce a week for the remainder of the five year treatment period.
 13. Themethod of claim 12 further comprising a second dose reduction step to 2micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b once a week for theremainder of the five year treatment period.
 14. The method of claim 13further comprising a third dose reduction step to 1 microgram/kg ofPEG₁₂₀₀₀ interferon alpha-2b once a week for the remainder of the fiveyear treatment period.
 15. The method of claim 1 wherein thetherapeutically effective weekly dose of PEG₁₂₀₀₀ interferon alphaadministered is about 200 micrograms to 250 micrograms of PEG₁₂₀₀₀interferon alpha-2a.
 16. A method of treating a patient having cutaneousmelanoma which has been surgically removed which comprises administeringto said patient an effective amount of PEG₁₂₀₀₀ interferon alpha once aweek for a time period sufficient to increase progression-free survivaltime; wherein the effective amount of PEG₁₂₀₀₀ interferon alphaadministered once a week is selected from the group consisting of about3.0 micrograms/kg to 9.0 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2band about 200 micrograms to 250 micrograms of PEG₁₂₀₀₀ interferonalpha-2a.
 17. The method of claim 16 wherein the effective amount ofPEG₁₂₀₀₀ interferon alpha administered once a week is about 3.0micrograms/kg to 9.0 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b. 18.The method of claim 17 wherein the therapeutically effective weekly doseof PEG₁₂₀₀₀ interferon alpha-2b is about 4.5 to about 6.5 micrograms/kgof PEG₁₂₀₀₀ interferon alpha-2b.
 19. The method of claim 18 wherein thetherapeutically effective weekly dose of PEG₁₂₀₀₀ interferon alpha-2b isabout 5.5 to about 6.5 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b.20. The method of claim 19 wherein the therapeutically effective weeklydose of PEG₁₂₀₀₀ interferon alpha-2b is about 8.0 micrograms/kg ofPEG₁₂₀₀₀ interferon alpha-2b.
 21. The method of claim 20 furthercomprising a dose reduction step such that 6.0 micrograms/kg of PEG₁₂₀₀₀interferon alpha-2b is administered once a week for eight weeks, andthen 3.0 or less micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b isadministered once a week for the remainder of a five year treatmentperiod.
 22. The method of claim 21 wherein the dose reduction step is to3 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b once a week for theremainder of the five year treatment period.
 23. The method of claim 22further comprising a second dose reduction step to 2 micrograms/kg ofPEG₁₂₀₀₀ interferon alpha-2b once a week for the remainder of the fiveyear treatment period.
 24. The method of claim 23 further comprising athird dose reduction step to 1 microgram/kg of PEG₁₂₀₀₀ interferonalpha-2b once a week for the remainder of the five year treatmentperiod.
 25. The method of claim 16 wherein the effective amount ofPEG₁₂₀₀₀ interferon alpha administered once a week is about 200micrograms to 250 micrograms of PEG₁₂₀₀₀ interferon alpha-2a.
 26. Themethod of claim 16 wherein the time period is at least about 100 weeks.27. A method of treating a patient having cutaneous melanoma whichcomprises administering to such a patient about 3.0 micrograms/kg toabout 9.0 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b once a week fora time period sufficient to increase the progression-free survival time.28. The method of claim 27 wherein the time period is about 100 weeks.29. The method of claim 27 wherein about 4.5 to about 6.5 micrograms/kgof PEG₁₂₀₀₀ interferon alpha-2b is administered once a week.
 30. Themethod of claim 29 wherein about 5.5 to about 6.5 micrograms/kg ofPEG₁₂₀₀₀ interferon alpha-2b is administered once a week.
 31. The methodof claim 30 wherein about 6.0 micrograms/kg of PEG₁₂₀₀₀ interferonalpha-2b is administered once a week.
 32. The method of claim 31 furthercomprising a dose reduction step such that 6.0 micrograms/kg of PEG₁₂₀₀₀interferon alpha-2b is administered once a week for eight weeks, andthen 3.0 or less micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b isadministered once a week for the remainder of a five year treatmentperiod.
 33. The method of claim 32 wherein the dose reduction step is to3 micrograms/kg of PEG₁₂₀₀₀ interferon alpha-2b once a week for theremainder of a five year treatment period.
 34. The method of claim 33further comprising a second dose reduction step to 2 micrograms/kg ofPEG₁₂₀₀₀ interferon alpha-2b once a week for the remainder of the fiveyear treatment period.
 35. The method of claim 34 further comprising athird dose reduction step to 1 microgram/kg of PEG₁₂₀₀₀ interferonalpha-2b once a week for the remainder of the five year treatmentperiod.